Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity

Dehghani, Mohammad Reza; Mehrjardi, Mohammad Yahya Vahidi; Dilaver, Nafi; Tajamolian, Masoud; Enayati, Samaneh; Ebrahimi, Parvin; Amoli, Mahsa M.; Farooqi, Sadaf; Maroofian, Reza

doi:10.1016/j.ejmg.2018.03.006

Cited by 17 publications

(12 citation statements)

References 16 publications

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“…Le Beyec et al reported resolving of central hypothyroidism from age 16 years onward and hypogonadism from age 19 years onward in a male patient (20). Dehghani et al reported that two affected males in a consanguineous family showed BMI normalization from puberty onset onward, in contrast to the affected females in this family who did not show improvement of BMI nor hypogonadotropic hypogonadism, suggesting a sex-specific effect might be present (29). However, Nizard et al reported resolving of hypogonadotropic hypogonadism in a female patient from age 18 years onward and occurrence of natural pregnancy 2 years after gastric bypass surgery (40), which challenges the assumption that hormonal disturbances only resolve in male patients.…”

Section: Discussionmentioning

confidence: 99%

“…Young age of known patients and absence of adult LepR deficiency patients in several large adult cohorts with early-onset obesity (6,7,8) could suggest that these patients decease before they are identified. This may occur due to the consequences of their severe obesity, but mortality in early childhood due to infections has also been reported (4,29). Long-term follow-up studies of the clinical course of LepR deficiency have however not yet been performed.…”

Section: Discussionmentioning

confidence: 99%

“…In total, 5175 records were screened (Fig. 1), of which 24 records presented unique patients with LepR deficiency and were eligible for inclusion (2,4,5,7,9,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35). From these 24 records, we identified n = 86 unique patients with LepR deficiency from 57 different families.…”

Section: Systematic Literature Search and Overview Of Published Casesmentioning

confidence: 99%

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Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

Kleinendorst

Abawi

Kamp

et al. 2020

European Journal of Endocrinology

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Objective Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing LepR deficiency is urgent. However, recognition is challenging and prevalence is unknown. We aim to elucidate the clinical spectrum and to estimate the prevalence of LepR deficiency in Europe. Design Comprehensive epidemiologic analysis and systematic literature review. Methods We curated a list of LEPR variants described in patients and elaborately evaluated their phenotypes. Subsequently, we extracted allele frequencies from the Genome Aggregation Database (gnomAD), consisting of sequencing data of 77 165 European individuals. We then calculated the number of individuals with biallelic disease-causing LEPR variants. Results Worldwide, 86 patients with LepR deficiency are published. We add two new patients, bringing the total of published patients to 88, of which 21 are European. All patients had early-onset obesity; 96% had hyperphagia; 34% had one or more pituitary hormone deficiencies. Our calculation results in 998 predicted patients in Europe, corresponding to a prevalence of 1.34 per 1 million people (95% CI: 0.95–1.72). Conclusions This study shows that LepR deficiency is more prevalent in Europe (n = 998 predicted patients) than currently known (n = 21 patients), suggesting that LepR deficiency is underdiagnosed. An important cause for this could be lack of access to genetic testing. Another possible explanation is insufficient recognition, as only one-third of patients has pituitary hormone deficiencies. With novel highly effective treatment emerging, diagnosing LepR deficiency is more important than ever.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Systematic Literature Search and Overview Of Published Casesmentioning

confidence: 99%

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Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

Kleinendorst

Abawi

Kamp

et al. 2020

European Journal of Endocrinology

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“…However, there are also reports of spontaneous puberty in patients with LEPR deficiency without surgery. Furthermore, a gender-specific effect on reproduction is currently discussed in patients with LEPR deficiency [21].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

Zorn¹,

Schnurbein²,

Kohlsdorf³

et al. 2020

Mol Cell Pediatr

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Background Rare genetic variations in the leptin-melanocortin signalling pathway can severely impair appetite regulation and cause extreme obesity in early childhood. Case presentation Our case reports describe the diagnostic and therapeutic procedures in a girl as well as in a non-related boy of non-consanguineous, German parents with severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour. Excessive weight gain within the first year of life initiated extensive diagnostics without finding a causal diagnosis. Furthermore, a wide range of intensive, interdisciplinary, and behavioural therapies for weight control were unsuccessful. Prior to bariatric surgery, the 18-year-old girl and the 14-year-old boy reached a BMI of 67.7 kg/m2 and 55.2 kg/m2, respectively. However, even surgical outcomes were unsatisfactory. A subsequently initiated genetic analysis including sequencing of the leptin receptor gene revealed compound heterozygous variants as a cause of the severe early-onset obesity in both patients (c.2598-3_2607delTAGAATGAAAAAG and c.2227 T>C; c.1874G>A and c.2051A>C). Both patients were enrolled in the clinical study RM-493-015 and treated with melanocortin receptor agonist setmelanotide. Currently, they are still on setmelanotide treatment in the extension trial RM-493-022. Conclusion Our case report illustrates the urgent necessity of early genetic diagnostics in children with severe early-onset obesity to avoid frustrating and potentially damaging therapies. Thus, genetic examination should precede bariatric surgery. In the future, several pharmacological therapies will be available for some forms of monogenetic obesity.

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“…It is interesting to see a sex-specific difference in outcomes in patients carrying biallelic LEPR mutations. Sex differences are more often described in patients with biallelic LEPR mutations [ 42 ]. However, no firm conclusions can be drawn on such a heterogeneous group, with only a small number of patients.…”

Section: Bariatric Surgery For the Treatment Of Non-syndromic Geneticmentioning

confidence: 99%

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders

et al. 2020

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Purpose of Review The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. Recent Findings In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. Summary There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients. Electronic supplementary material The online version of this article (10.1007/s11892-020-01327-7) contains supplementary material, which is available to authorized users.

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Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity

Cited by 17 publications

References 16 publications

Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders

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